Anxiety disorders emerge in adolescence and are marked by dysfunction of limbic regions, including the pre- frontal cortex, amygdala and striatum. The amygdala has consistently been shown to be hyperactive among patients with anxiety disorders, and has connections with the pre-frontal cortex and the striatum. Projections from the pre-frontal cortex inhibit the amygdala, while amygdalostriatal projections detect salience and assign positive motivational valence to complex stimuli to create a behavioral response. The connectivity of the pre- frontal cortex-amygdala-striatum circuit has not been well characterized, and we propose studies aimed at understanding how this circuit is disrupted by anxiety disorders in adolescents, as well as adolescents with behavioral inhibition, a significant risk factor for anxiety. To better understand these connections, we first propose neuroanatomic studies in non-human primates that chart the subregions of the pre-frontal cortex through individual amygdalar nuclei to regions of the striatum using a bidirectional tract-tracing technique. We will then use these anatomic results to create seeds for regions of interest in a connectivity analysis of the pre- frontal cortex, amygdala and striatum in human adolescents anticipating monetary rewards and punishments. The connectivity will be compared in a healthy group of adolescents, as well as adolescents with anxiety disorders and behavioral inhibition, in order to understand neurobiologic changes of disease and vulnerability. We hypothesize that specific subregions of the pre-frontal cortex will project differentially to the amygdalostriatal pathways, and that those with anxiety will have decreased connectivity from their pre-frontal cortex to amygdala, with increased connectivity between their amygdalostriatal pathways. Aim 1 will map the projections from subregions of the pre-frontal cortex through amygdalar nuclei to regions of the striatum. Aim 1A will map the pre-frontal cortex-amygdala projections, while Aim 1B will map the amygdalostriatal projections within the same animal used for Aim 1A. Aim 2 will compare the functional connectivity of the pre-frontal cortex-amygdala-striatum circuit in human adolescents with anxiety disorders or behavioral inhibition with normal, healthy adolescents, using functional magnetic resonance imaging (fMRI) and a task of anticipation of monetary rewards and losses. PUBLIC HEALTH RELEVANCE: Anxiety disorders emerge during adolescence and are marked by dysfunction of the pre- frontal cortex, amygdala and striatum. We are researching how these regions are connected in adolescents with anxiety disorders and adolescents vulnerable to adolescent disorders, specifically those with behavioral inhibition.